Search

OBJECTIVES:Theβ-adrenergic receptor (βAR) genes are candidate genes for obesity because of their roles in energy homeostasis and promotion of lipolysis in human adipose tissue. Objective is to determine the association between obesity and polymorphisms in genes of theβ1AR (ADRB1),β2AR (ADRB2),β3AR (ADRB3), Gs protein alpha (GNAS1), to which all threeβ-receptors couple and the G proteinβ3 subunit (GNB3), to whichβ3ARs couple.DESIGN:A case–control genetic association study.SUBJECTS:A total of 643 black or white women enrolled in Women's Ischemia Syndrome Evaluation (WISE) study.MEASUREMENTS:Genotypes were determined by PCR with single primer extension. Associations between genotype and body mass index (BMI), waist-to-hip ratio (WHR), waist circumference, and obesity were made.RESULTS:Polymorphisms in the threeβAR genes, GNAS1, and GNB3 were not associated with BMI, WHR, waist circumference, or obesity. Linear and logistic regression analyses found no contribution of either genotype or haplotype with anthropometric measurements or obesity.CONCLUSIONS:Our study suggests that among American women with suspected coronary heart disease, polymorphisms in theβARs and their G-protein-coupled receptors do not contribute to increased BMI, WHR, waist circumference, or obesity. Given that 50% of all women die from coronary heart disease, and a higher percentage have heart disease during their lifetime, our results are likely generalizable to many American women.International Journal of Obesity (2005) 29, 746–754. doi:10.1038/sj.ijo.0802978 Published online 3 May 2005 [ABSTRACT FROM AUTHOR]

Background: Polymorphisms in the α2c adrenergic receptor (ADRA2C) and the β1 adrenergic receptor (ADRB1) genes have been suggested to act synergistically in heart failure (HF) risk. We tested their association (and synergism) with β-blocker (BB) response in HF.Methods: Left ventricular ejection fraction (EF) was determined by echocardiography at baseline and after 5-6 months of metoprolol CR/XL therapy in 54 patients with systolic HF. ADRB1 Arg389Gly and ADRA2C 322-325 Insertion/Deletion (Ins/Del) polymorphisms were determined by pyrosequencing. Linear regression modeling of end of study EF was done with patient age, race, genotypes, HF etiology, spironolactone, digoxin, and furosemide use and final metoprolol CR/XL dose considered in the model. EF response by genotype was compared by t-tests and ANOVA.Results: Significant predictors of the end study EF were baseline EF, Del-carrier status, Arg389Arg genotype and age. The combination of both genotypes (Arg389Arg & Del-carrier) (Gp1) showed the greatest EF change. Adjusting for baseline EF and age, the end study EF of Gp1 was significantly different from the 3 other groups (overall p=0.0012) (table).Conclusions: Polymorphisms in the ADRB1 and ADRA2C genes synergistically influence the left ventricular reverse remodeling response to β-blockers in HF.Clinical Pharmacology & Therapeutics (2005) 79, P31–P31; doi: 10.1016/j.clpt.2005.12.113 [ABSTRACT FROM AUTHOR]

Background: The cardiovascular effects of ertugliflozin, an inhibitor of sodium-glucose cotransporter 2, have not been established.Methods: In a multicenter, double-blind trial, we randomly assigned patients with type 2 diabetes and atherosclerotic cardiovascular disease to receive 5 mg or 15 mg of ertugliflozin or placebo once daily. With the data from the two ertugliflozin dose groups pooled for analysis, the primary objective was to show the noninferiority of ertugliflozin to placebo with respect to the primary outcome, major adverse cardiovascular events (a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke). The noninferiority margin was 1.3 (upper boundary of a 95.6% confidence interval for the hazard ratio [ertugliflozin vs. placebo] for major adverse cardiovascular events). The first key secondary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure.Results: A total of 8246 patients underwent randomization and were followed for a mean of 3.5 years. Among 8238 patients who received at least one dose of ertugliflozin or placebo, a major adverse cardiovascular event occurred in 653 of 5493 patients (11.9%) in the ertugliflozin group and in 327 of 2745 patients (11.9%) in the placebo group (hazard ratio, 0.97; 95.6% confidence interval [CI], 0.85 to 1.11; P<0.001 for noninferiority). Death from cardiovascular causes or hospitalization for heart failure occurred in 444 of 5499 patients (8.1%) in the ertugliflozin group and in 250 of 2747 patients (9.1%) in the placebo group (hazard ratio, 0.88; 95.8% CI, 0.75 to 1.03; P = 0.11 for superiority). The hazard ratio for death from cardiovascular causes was 0.92 (95.8% CI, 0.77 to 1.11), and the hazard ratio for death from renal causes, renal replacement therapy, or doubling of the serum creatinine level was 0.81 (95.8% CI, 0.63 to 1.04). Amputations were performed in 54 patients (2.0%) who received the 5-mg dose of ertugliflozin and in 57 patients (2.1%) who received the 15-mg dose, as compared with 45 patients (1.6%) who received placebo.Conclusions: Among patients with type 2 diabetes and atherosclerotic cardiovascular disease, ertugliflozin was noninferior to placebo with respect to major adverse cardiovascular events. (Funded by Merck Sharp & Dohme and Pfizer; VERTIS CV ClinicalTrials.gov number, NCT01986881.). [ABSTRACT FROM AUTHOR]

5-{2-[4-(3,4-Difluorophenoxy)-phenyl]-ethylsulfamoyl}-2-methyl-benzoic acid (1) is a novel, potent, and selective agonist of the peroxisome proliferator-activated receptor alpha (PPAR-alpha). In preclinical species, compound 1 demonstrated generally favourable pharmacokinetic properties. Systemic plasma clearance (CLp) after intravenous administration was low in Sprague-Dawley rats (3.2 +/- 1.4 ml min(-1) kg(-1)) and cynomolgus monkeys (6.1 +/- 1.6 ml min(-1) kg(-1)) resulting in plasma half-lives of 7.1 +/- 0.7 h and 9.4 +/- 0.8 h, respectively. Moderate bioavailability in rats (64%) and monkeys (55%) was observed after oral dosing. In rats, oral pharmacokinetics were dose-dependent over the dose range examined (10 and 50 mg kg(-1)). In vitro metabolism studies on 1 in cryopreserved rat, monkey, and human hepatocytes revealed that 1 was metabolized via oxidation and phase II glucuronidation pathways. In rats, a percentage of the dose (approximately 19%) was eliminated via biliary excretion in the unchanged form. Studies using recombinant human CYP isozymes established that the rate-limiting step in the oxidative metabolism of 1 to the major primary alcohol metabolite M1 was catalysed by CYP3A4. Compound 1 was greater than 99% bound to plasma proteins in rat, monkey, mouse, and human. No competitive inhibition of the five major cytochrome P450 enzymes, namely CYP1A2, P4502C9, P4502C19, P4502D6 and P4503A4 (IC50's > 30 microM) was discerned with 1. Because of insignificant turnover of 1 in human liver microsomes and hepatocytes, human clearance was predicted using rat single-species allometric scaling from in vivo data. The steady-state volume was also scaled from rat volume after normalization for protein-binding differences. As such, these estimates were used to predict an efficacious human dose required for 30% lowering of triglycerides. In order to aid human dose projections, pharmacokinetic/pharmacodynamic relationships for triglyceride lowering by 1 were first established in mice, which allowed an insight into the efficacious concentrations required for maximal triglyceride lowering. Assuming that the pharmacology translated in a quantitative fashion from mouse to human, dose projections were made for humans using mouse pharmacodynamic parameters and the predicted human pharmacokinetic estimates. First-in-human clinical studies on 1 following oral administration suggested that the human pharmacokinetics/dose predictions were in the range that yielded a favourable pharmacodynamic response.

Our objective was to determine if beta(1)-adrenergic receptor (beta(1)-AR) and beta(2)-AR gene polymorphisms influence heart rate (HR), systolic blood pressure (SBP) and diastolic blood pressure (DBP) response to dobutamine during dobutamine stress echocardiography (DSE). Patients (n=163) undergoing clinically indicated DSE were enrolled. Dobutamine doses were titrated from 5 to 40 microg kg(-1) min(-1) at 3 min intervals and HR, SBP and DBP were measured. Genotypes were determined for beta(1)-AR Ser49Gly, beta(1)-AR Arg389Gly, beta(2)-AR Arg16Gly and beta(2)-AR Gln27Glu polymorphisms by polymerase chain reaction-restriction fragment length polymorphism analysis, pyrosequencing and single primer extension methods. beta(2)-AR Glu27 homozygotes had a greater HR response at the highest dobutamine dose than Gln27 carriers (P=0.002). Beta(2)-AR Gly16 homozygotes had a lower HR response during 5-30 microg kg(-1) min(-1) of the dobutamine infusion protocol compared to Arg16 carriers (P=0.03). Differences in SBP by beta(2)-AR codon 16 genotype and DBP by beta(1)-AR codon 389 genotype were found at baseline and were maintained throughout DSE (P=0.06 and 0.02, respectively). However, the magnitude of SBP and DBP response to dobutamine did not differ significantly by beta(2)-AR codon 16 or beta(1)-AR codon 389 genotypes, respectively. These data suggest that the four selected beta(1)- and beta(2)-AR polymorphisms do not substantially influence the magnitude of hemodynamic response to dobutamine during DSE.

Clinical studies have solidified the utility of digoxin in patients with left ventricular dysfunction and normal sinus rhythm. No definitive data have been published to clarify the range of serum digoxin concentrations associated with clinical benefit. The traditional therapeutic range of 0.8-2.0 ng/ml was developed originally to classify digoxin toxicity, not efficacy. In addition, this reference range was used before publication of the Digitalis Investigators Group trial. Clinical and neurohormonal studies have attempted to characterize serum concentrations that are associated with clinical efficacy.

The theory that pruritus from cholestasis is due to increased opiate tone appears to have merit, based on the results of the clinical trials presented above. However, although opioid antagonists relieve itching to a large extent, the itching usually is not abolished completely. Several factors may explain this lack of complete relief. The doses used in the clinical trials may have been insufficient, or duration of therapy may have been short. It is also possible that nonopioid mechanisms contribute to pruritus from cholestasis. Although effective, naloxone therapy has several limitations for long-term use, including a short half-life and large first-pass metabolism, which necessitates parenteral administration. Intravenous administration is clearly not practical for a chronic disease. Nalmefene treatment has several advantages over naloxone, with both prolonged duration of action and increased potency at the opioid receptor level. However, nalmefene is available only as a parenteral product in the US. The nalmefene studies are limited by their small sample size and short follow-up periods. Additionally, two of the studies are available in abstract form only. Based on two clinical studies, naltrexone therapy appears promising. Gradual dose titration from 25 mg/d up to a maximum of 50 mg/d may minimize withdrawal reactions. Further long-term clinical trials using objective measures that compare opioid antagonists with other therapies are needed to clearly establish the role of these agents. Potential tachyphylaxis from long-term use of opioid antagonists requires further investigation. Combination therapy may also be required, since monotherapy with either opioid antagonists or other therapies have failed to completely relieve the pruritus caused by cholestasis. Given the potential for severe withdrawal reactions, opioid antagonists should be reserved for patients refractory to other treatments.

Veno-occlusive disease (VOD) of the liver is a potentially life-threatening complication that usually occurs secondary to high dose-chemotherapy with or without total body irradiation as preparative therapy for bone marrow transplantation. The key event in the development of VOD is damage to the vascular endothelium in the liver, which produces a hypercoagulable state triggering the clotting cascade. Factor VIII and fibrinogen are deposited in the hepatic venules, leading to obliteration of the venules. Tissue plasminogen activator (t-PA) converts fibrin-bound plasminogen to plasmin, thereby producing clot lysis. Review of the literature suggests that t-PA can be administered safely, with some limitations, for the treatment of VOD.

The use of MPA in patients with OSA is limited. Instead, patients with OSA should be encouraged to abstain from alcohol and respiratory depressive agents, and avoid sleeping in the supine position. In general, patients with OSA are most effectively treated with CPAP and/or surgery. Patients need to be encouraged to maintain ideal body weight, since this has been associated with a marked reduction in symptoms. For patients who are not surgical candidates or refuse to use CPAP, drug therapy may be beneficial. Fluoxetine has been shown to be as effective as protriptyline, and is better tolerated. However, further study is needed to determine whether selective serotonin-reuptake inhibitors are beneficial in treating OSA. Therefore, MPA therapy should be reserved for hypercapnic patients who refuse other modalities of treatment. The potential long-term adverse effects of MPA must be addressed before initiating therapy in men with OSA.